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Abstract
Purpose
Urinary cytokines are proposed to predict the urodynamic findings and outcome of intradetrusor botulinum neurotoxin type A injection (iBoNT-Ai) in children with myelodysplasia. The relationship between urinary brain-derived neurotrophic factor (BDNF) and neurogenic and non-neurogenic detrusor overactivity (NDOA) has been shown, as...
Context in source publication
Context 1
... to baseline, urine BDNF levels decreased at 1 and 3 months (both p ¼ 0.006, figs. 1 and 2). We compared findings in children with preoperative Pdetmax above and below 40 cm H 2 O (table 2), and in those with DLPP and no DLPP postoperatively (table 3). Interestingly urine BDNF levels and their reduction did not differ statistically between children with Pdetmax above and below 40 cm H 2 O in any time period preoperatively or postoperatively (p >0.05, table 4). ...Similar publications
Lingual dystonia is a debilitating type of oromandibular dystonia characterized by involuntary, often task-specific, contractions of the tongue muscle activated by speaking or eating. Botulinum neurotoxin (BoNT) has been used to treat lingual dystonia; however, it is known to cause serious complications, such as dysphasia and aspiration. The purpos...
Citations
... CRP, C-reactive protein; DO, detrusor overactivity; LUT, lower urinary tract; LUTS, lower urinary tract symptoms; NGF, nerve growth factor; NS, nervous system. Pediatric neurogenic population has been another target of urine biomarker research aiming to predict upper urinary tract damage response to botulinum neurotoxin injection 45,46 and bladder compliance 47 studying urinary NGF, TGF-β1, TIMP-2, and BDNF. A very recent systematic review on pediatric population has just been published pointing that prospective studies with larger sample sizes are needed to better understand the potential of urinary biomarkers to reflect urodynamic and clinical findings in children with LUTD. ...
Introduction
Overactive bladder (OAB) and underactive bladder (UAB) could be associated with metabolic syndrome, affective disorders, sex hormone deficiency, changes in urinary microbiota, functional gastrointestinal disorders, or autonomic nervous system dysfunction.
Objectives
The aim of this Think Tank was to provide a guide on how to investigate OAB and/or detrusor underactivity (DU) patients to better clarify the underlying pathophysiology and possibly personalize the treatment.
Methods
A compendium of discussion based on the current evidence related to phenotyping patients with OAB or DU using urodynamic tests, functional neuro‐imaging, urinary markers, and microbiome.
Results and Conclusions
The article emphasizes the critical significance of adopting a comprehensive yet tailored approach to phenotyping patients with lower urinary tract (LUT) symptoms, such as OAB and UAB. The intricate interplay between the LUT and various factors, metabolic, neurological, psychological, and gastrointestinal can define unique LUT profiles, enabling personalized therapies to replace the one‐size‐fits‐all approach.
... Identifying those who may not respond to a second injection, particularly in children, is important for a decision algorithm. Brain-derived neurotrophic factor, as a urinary marker, may potentially identify which patients have failed initial Botox therapy, without the need for invasive urodynamics, which would be helpful to redirect treatment strategy [57]. ...
Purpose of review:
Botulinum neurotoxin A (BoNT/A), or Botox, is a popular option for overactive bladder (OAB) and neurogenic bladder (NGB) with or without incontinence. This review aims to discuss the clinical outcomes of BoNT in adult and pediatric bladder conditions, and introduces the potential benefit of novel, engineered neurotoxins beyond BoNT/A.
Recent findings:
A large volume of evidence supports the use of Botox for OAB (to reduce urgency, frequency and incontinence episodes), and for NGB (to decrease incontinence and improve bladder capacity and detrusor pressures). Botox is now also Food & Drug Administration (FDA)-approved for pediatric neurogenic detrusor overactivity. However, urinary retention, diminished response over time and treatment failures are prevalent issues with Botox. Modifying natural BoNTs or forming chimeric toxins are alternatives to BoNT/A that may have higher efficacy and lower side-effect profile. One example is BoNT/BMY-WW. This novel engineered toxin binds to a more commonly expressed synaptotagmin receptor, with potentially more potent paralytic effect and less capacity for systemic diffusion.
Summary:
Novel engineered neurotoxins may be the next frontier in OAB and NGB therapy.
... However, more comprehensive studies in this field are necessary, as well as in the research field about the usefulness of urinary cytokines in the planning for BTA treatment. [48][49][50] In conclusion, BTA is a clinically and urodynamically effective and safe treatment for NDO in children. Patients with fibrotic, acontractile bladders with poor bladder compliance (without DO) and children with a very small initial bladder capacity seemed to respond poorly or not at all to BTA treatment. ...
Special birth defects and neurological diseases can cause neurogenic detrusor overactivity (NDO). First-line pharmacotherapy is the antimuscarinic therapy, which can be limited by side effects or non-effectiveness. Therefore, pharmacological treatment of NDO in children includes off-label use of intravesical injections of botulinum toxin type A (BTA). In this review article, various clinical studies in which BTA was used for the treatment of NDO of different etiologies in children are discussed, including studies about children with acquired NDO. An electronic literature search was performed using PubMed, and studies published prior to March 2019 are reported. BTA injections are a clinically and urodynamically effective and safe treatment for NDO in children. The treatment is also important in protecting the upper urinary tract from damage and improving concomitant bowel dysfunctions. Fibrotic, acontractile bladders with poor bladder compliance and/or a very small initial bladder capacity and/or the presence of an open bladder neck all contributed to poor responses. A combined injection into the detrusor and external urethral sphincter may improve the clinical outcome in the detrusor-sphincter dyssynergia. New application methods are promising, such as the electromotive drug administration, to avoid general anesthesia. Furthermore, the minimal clinically effective dosage, inclusion criteria, and prognostic factors remain to be established.
Objective: The aim of this study was to investigate whether urinary glycosaminoglycans (GAG) levels reflect clinical status in men with lower urinary tract symptoms and if they could be used as a marker in management of overactive bladder (OAB). Methods: A total of 34 patients were recruited who were admitted with LUTS and diagnosed as having clinically bladder outlet obstruction (BOO) due to prostate enlargement. These newly diagnosed, never treated patients underwent routine investigation, consisting of history, physical examination, PSA, ultrasound, uroflowmetry, assessment of symptoms scored by both International Prostate Symptom Score (IPSS) and Marmara- Overactive Bladder Questionnaire (M-OBQ). The patients were divided into two groups as those with an initial M-OBQ score < 12 (group 1) and ≥ 13 (group 2). Alfa blocker was initiated in eligible patients. Further evaluations included prostate volume measurement, pre- and post-treatment urinary GAG levels, IPSS and M-QAOB values and maximum urine flow rate (Qmax). Results: Before treatment, urinary GAG level was 21.5 mg/gCr (6.1-45.5) in Group 1, and 23.35 mg/gCr (15.6-32.6) in Group 2 (p =0.845). After the treatment, the GAG level in Group 1 and Group 2 were found to be 19.8 mg/gCr (7.4-70.5) and 18 (7.6- 41.7), respectively (p = 0.511). No difference in GAG levels was found in subgroup analysis for patients with or without OAB. Conclusions: In recent years, there have been many studies investigating the relationship between LUTS and urinary markers. However, in our prospective study, no relationship was found between pre- and post- treatment urinary GAG levels in patients with LUTS with or without OAB.
Aim
The aim of this systematic review is to assess urinary biomarkers studied in children with neurogenic and non‐neurogenic lower urinary tract dysfunction (LUTD).
Materials and Methods
The systematic review was conducted in accordance with the PRISMA guidelines. The screening was performed on PUBMED without any publication date limitation. Only original articles were included. Parameters related to the following topics were obtained: study design, characteristics of participants, number of participants, age, control group, types of biomarkers, measurement technique in urine, subgroup analysis, urodynamic findings, and outcome. Dutch Cochrane Checklist (DCC) and level of evidence by EBRO platform were used for quality assessment. Meta‐analysis was performed with the Comprehensive Meta‐Analysis Version 4 program.
Results
A total of 494 studies were screened and 16 studies were included. 11 (68.75%) were conducted in children with non‐neurogenic LUTD and 5 (31.25%) neurogenic LUTD. Nerve growth factor (NGF) was evaluated in 12 studies, brain‐derived neurotrophic factor (BDNF) in 5, Tissue Inhibitor of Metalloproteinase‐2 (TIMP‐2) in 2, transforming growth factor beta‐1 (TGF Beta‐1) in 2, neutrophil gelatinase‐associated lipocalin (NGAL) in 1, and Aquaporin‐2 in 1. According to DCC, 10 (62.5%) articles were evaluated on 4 (37.5%) items and 4 articles on 5 items. The average score was 3.91+/−0.56. The level of evidence was found as B for 13 (81.25%) articles and C for 3 (18.75%). In meta‐analysis, urinary NGF levels in children with non‐neurogenic LUTS were significantly higher than in the healthy control group (Hedges's g = 1.867, standard error = 0.344, variance = 0.119, p = 0.0001).
Conclusion
Urinary biomarkers are promising for the future with their noninvasive features. However, prospective studies with larger sample sizes are needed to better understand the potential of urinary biomarkers to reflect urodynamic and clinical findings in children with LUTD.
Aim:
The purpose of our study was to evaluate the relationship of urinary brain-derived neurotrophic factor (BDNF), adenosine triphosphate (ATP), matrix metallopreteinase-2 (MMP-2) with urodynamic findings and upper urinary tract deterioration (UUTD) in children with myelodysplasia.
Materials and methods:
Children with myelodysplasia evaluated in outpatient clinic between 2022 and 2023 were included. All patients underwent urinary ultrasonography, voiding cystourethrography, urodynamics, and DMSA scintigraphy. Urine samples were collected before urodynamics. Control urine was collected from 10 healthy children. Urinary biomarker values of patients and controls were compared, and subgroup analysis was performed.
Results:
The median age of 40 children (26 girls) included in the study was 108 (8-216) months, and the control group (six girls) was 120 (60-154) (p = 0.981). Urinary BDNF, MMP-2, and ATP were found to be significantly higher in children with myelodysplasia compared to the control (p = 0.007, p = 0.027, p = 0.014, respectively). The three biomarker values were similar in children with bladder compliance below or above 10 cmH2O/mL (p = 0.750, p = 0.844, p = 0.575). No difference was found in terms of UUTD in all three biomarkers (p = 0.387, p = 0.892, p = 0.705). A negative correlation was found between urinary ATP and compliance (p < 0.05).
Conclusion:
In this study, all three biomarkers were found to be higher in children with myelodysplasia than in controls. There was a negative correlation between urinary ATP and compliance. Urinary biomarkers may contribute the follow-up of children with neurogenic lower urinary tract deterioration in future with their noninvasive features. However, the lack of standardization and the inability to reliably predict risky groups are important shortcomings of urinary biomarkers.
Purpose:
OnabotulinumtoxinA is an approved treatment for neurogenic detrusor overactivity in adults inadequately managed with anticholinergics, and more recently was approved in children on the basis of a phase 3, 48-week, single-treatment study (NCT01852045). Given the paucity of long-term pediatric data, we report on the continued safety in these patients after repeated onabotulinumtoxinA treatment.
Materials and methods:
This was a multicenter, double-blind, repeat-treatment extension study (NCT01852058) in patients who entered from the preceding single-treatment study. Data were integrated across both studies. All patients (5-17 years) used clean intermittent catheterization and could receive dose escalations based on response to preceding treatment (50 U, 100 U, or 200 U onabotulinumtoxinA [not to exceed 6 U/kg]).
Results:
Overall, 95, 90, 55, and 11 patients received 1, 2, 3, and 4 treatments with onabotulinumtoxinA, respectively, and median (quartiles) duration of follow-up was 82 (65, 94) weeks. The safety profile was similar across doses and after repeat treatments. The most common treatment-emergent adverse event during cycles 1, 2, and 3 was urinary tract infection (31%, 34%, 22%). Three serious treatment-emergent adverse events related to study treatment (3/95; 3.2%) were reported during the study, which were all cases of urinary tract infection. Annualized urinary tract infection rates post-treatment were similar to pre-screening rates. There were no cases of autonomic dysreflexia, neutralizing antibodies, and treatment-emergent adverse events related to distant spread of toxin.
Conclusions:
OnabotulinumtoxinA continued to be well tolerated after repeated treatments in pediatric neurogenic detrusor overactivity patients with similar safety profiles across dose groups. Treatment-emergent adverse events were primarily urological with no new safety concerns.
Radical prostatectomy can alter the anatomy of the urinary bladder. We aimed to evaluate bladder function before and 4 months after radical prostatectomy using the urodynamic test and overactive bladder (OAB) symptom score. Among 70 prospectively enrolled patients, 61 patients completed the study. In the urodynamic test, bladder capacity and compliance did not change, the frequency of involuntary detrusor contraction decreased, the maximum flow rate and bladder outlet obstruction index improved, and the maximum urethral closure pressure (MUCP) deteriorated. Further evaluation of urodynamic parameters according to changes in symptoms was made. Although change in bladder compliance was correlated with changes in OAB symptoms, not the relative change of bladder compliance but the relative change in the MUCP was reliable factor when OAB symptoms were deteriorated. In general, prostatectomy did not deteriorate the condition of the detrusor; rather, change in the MUCP could be responsible for postprostatectomy OAB.
Purpose:
Storage-phase bladder dysfunction can develop after pelvic radiotherapy. As the alpha-1d adrenoreceptor (a1d-AR) is dominant in the human detrusor, we aimed to investigate the effect of an a1d-AR antagonist on bladder dysfunction after pelvic radiotherapy in a rat model.
Materials and methods:
Twenty-four female Wistar rats were used. Eight rats (14-15 weeks, 250-300 g) were randomized to three groups (normal reference group, radiation alone group and radiation plus naftopidil group). An 18-Gy dose of radiotherapy was applied to the radiation alone and radiation plus naftopidil groups. Naftopidil (20 mg/kg) was administered daily to the radiation plus naftopidil group. Four weeks after radiation, all rats underwent cystometry and were killed for reverse transcription polymerase chain reaction to detect mRNAs [a1d-AR, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF)], Western blot to detect proteins (a1d-AR, extracellular-signal-regulated kinase, BDNF and VEGF) and immunohistochemistry.
Results:
Compared to the radiation alone group, (1) the decrease in the mRNA and protein expression of a1d-AR and VEGF was ameliorated, (2) the increase in the expression of BDNF mRNA and proteins such as extracellular-signal-regulated kinase and BDNF was suppressed, (3) submucosal thickness and vascularity on immunohistochemistry were improved, and (4) the baseline intravesical pressure and intercontraction interval in cystometry were ameliorated in the radiation plus naftopidil group.
Conclusion:
Administration of an a1d-AR antagonist could improve storage-phase bladder dysfunction after radiotherapy not only by upregulating a1d-AR, which might decrease bladder compliance, but also by enhancing vascularity, which might protect the urinary bladder from chronic ischemic inflammation.
Purpose:
We retrospectively evaluated the efficacy of botulinum neurotoxin A (BoNT-A) on vesicoureteral reflux (VUR), continence status, and urodynamic parameters in children with myelodysplasia who were not responsive to standard conservative therapy.
Methods:
The study included 31 children (13 boys, 18 girls) with a mean age of 9.2±2.3 years (range, 5-14 years) with myelodysplasia, retrospectively. All children were fully compatible with clean intermittent catheterization (CIC) and did not respond to the maximum tolerable anticholinergic dose. All children received an intradetrusor injection of 10 U/kg (maximum, 300 U) of BoNT-A into an infection-free bladder. All patients had VUR (22 unilateral, 9 bilateral) preoperatively. The grade of reflux was mild (grades 1, 2), intermediate (grade 3), and severe (grades 4, 5) in 25, 7, and 8 ureters, respectively.
Results:
The mean maximum bladder capacity increased from 152.9±76.9 mL to 243.7±103 mL (P<0.001), and the maximum detrusor pressure decreased from 57±29.4 cm H2O to 29.6±13.9 cm H2O (P<0.001). After BoNT-A treatment, 16 refluxing ureters (40%) completely resolved, 17 (42.5%) improved, 5 (12.5%) remained unchanged, and 2 (5%) became worse. Of the 31 children with urinary leakage between CICs, 22 (71%) became completely dry, 6 (19%) improved, and 3 (10%) experienced partial improvement.
Conclusion:
In children with myelodysplasia, we were able to increase bladder capacity, enhance continence, and prevent VUR by using intradetrusor BoNT-A injections. Although our results are promising, a larger group of long-term prospective studies are warranted to investigate this method of treatment.
